The last two decades have witnessed a striking increase in obesity, atherosclerosis, type II diabetes, and hypertension, all associated with metabolic syndrome. The underlying molecular defects contributing to metabolic syndrome are poorly defined. Complex regulatory mechanisms and interplay of different organs in guiding metabolism and lipid/energy homeostasis will necessitate studies in the context of whole organisms. We are proposing to investigate conserved mechanisms of regulation of lipid homeostasis in the nematode Caenorhabditis elegans. Many mammalian signaling pathways and regulatory circuitries modulating energy and lipid homeostasis, such as the insulin signaling pathway and the transcription factor SREBP, an important regulator of genes involved in cholesterol and fatty acid homeostasis, are conserved in C. elegans. C. elegans also has several advantages over more complex model systems, including short generation time and the ease of whole-organism RNAi screens. The Specific Aims are: 1. To determine the role of the SREBP homolog SBP-1 and cognate co-activators in regulation of lipid homeostasis in C. elegans. 2. To evaluate the role of the insulin/IGF-1 signaling pathway in regulating SBP-1 and C. elegans lipid homeostasis. 3. To identify novel regulators of fatty acid desaturation and lipid homeostasis in C. elegans. We propose to perform RNAi-based screens to identify novel conserved regulators of lipid homeostasis. The long-term objectives are to identify and characterize key conserved regulators of lipid biology that could contribute to dysregulation of energy/lipid homeostasis and metabolic syndrome in humans.